CYSTEINE-TO-ARGININE POINT MUTATION IN A HYBRID 8-CYSTEINE DOMAIN OF FBN1 - CONSEQUENCES FOR FIBRILLIN AGGREGATION AND MICROFIBRIL ASSEMBLY

Mutations in the FBN1 gene encoding the microfibrillar glycoprotein fi brillin cause Marfan syndrome, a relatively common autosomal dominant connective tissue disease, Causative FBN1 mutations appear to be dispe rsed throughout the coding frame, and to date no predictable genotype : phenotype correlations have emerged, We have identified a point muta tion within an eight-cysteine 'hybrid' motif of the fibrillin polypept ide which results in the substitution of an arginine for a cysteine, i n a patient severely affected in the cardiovascular, skeletal and ocul ar systems. We have utilised cell cultures from various tissues of thi s patient to investigate the effects of this mutation on fibrillin exp ression and deposition, and the consequences in terms of microfibril a ssembly and organisation. We have established that there is no differe nce in the expression of normal and mutant alleles, and fibrillin synt hesis, secretion and deposition are also normal. However, the rate of fibrillin aggregation is reduced and microfibrillar assemblies are bot h remarkably scarce and morphologically abnormal. These data clearly d emonstrate that the mutated allele interferes with normal assembly, an d strongly implicate this particular region of the fibrillin-1 molecul e in stabilising microfibrillar assemblies.